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Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.

ABSTRACT: Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

SUBMITTER: Nair RP

PROVIDER: S-EPMC2745122 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.

Nair Rajan P RP Duffin Kristina Callis KC Helms Cynthia C Ding Jun J Stuart Philip E PE Goldgar David D Gudjonsson Johann E JE Li Yun Y Tejasvi Trilokraj T Feng Bing-Jian BJ Ruether Andreas A Schreiber Stefan S Weichenthal Michael M Gladman Dafna D Rahman Proton P Schrodi Steven J SJ Prahalad Sampath S Guthery Stephen L SL Fischer Judith J Liao Wilson W Kwok Pui-Yan PY Menter Alan A Lathrop G Mark GM Wise Carol A CA Begovich Ann B AB Voorhees John J JJ Elder James T JT Krueger Gerald G GG Bowcock Anne M AM Abecasis Gonçalo R GR

Nature genetics 20090125 2

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes inv ...[more]

PMID: 19169254

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Project description:BackgroundPsoriasis is a persistent inflammatory dermatological disorder. Tanshinone IIA (tan-IIA) is a biologically active compound in the self-made Xiao-Yin decoction (SMXYD) and exhibits diverse biological properties, such as anti-proliferative and anti-inflammatory effects. The objective of this investigation was to assess the potential of tan-IIA as a therapeutic agent against psoriasis.MethodsNetwork pharmacology was employed to ascertain the active constituents and potential pathways associated with SMXYD and psoriasis. We conducted CCK-8, qRT-PCR, and western blotting to assess the proliferation of HaCaT keratinocytes and the expression of IL-17/IL-23 and PTGS2/NF-κB/AP-1 pathways. Additionally, we used H&E staining, western blotting, and ELISA to evaluate the therapeutic effects and signaling pathways of tan-IIA in psoriasis-like mice induced by imiquimod (IMQ).ResultsNetwork pharmacology analysis identified eight hub compounds. The Th17/IL-17 signaling was found to be a potential therapeutic pathway of SMXYD against psoriasis, with JUN (AP-1) as the core molecule. Next, PTGS2 was selected as the target of tan-IIA against psoriasis using network pharmacology analysis. Molecular docking showed a high affinity between PTGS2 and tan-IIA. Tan-IIA treatment attenuated M-5-induced hyperproliferation and inflammation in HaCaT keratinocytes. Additionally, Tan-IIA downregulated the PTGS2/NF-κB/AP-1 pathway in HaCaT keratinocytes. In the IMQ-induced psoriasis-like mouse, tan-IIA significantly reduced the severity of skin lesions and downregulated the PTGS2/NF-κB/AP-1 pathway. Moreover, the combination of methotrexate (MTX) and tan-IIA further inhibited the IL-17/IL-23 and PTGS2/NF-κB/AP-1 pathways.ConclusionThe administration of tan-IIA has shown a positive effect on psoriasis by inhibiting the IL-17/IL-23 and PTGS2/NF-κB/AP-1 pathways. The findings suggest that it has promising qualities that make it a potential candidate for the development of future anti-psoriatic agents.

Dataset Information

Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.

Publications

Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.

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